Therapeutic agent for fibrosis

ABSTRACT

Provided are a therapeutic agent and a pharmaceutical composition exerting an excellent prophylactic or therapeutic effect on fibrosis and symptoms associated with fibrosis. The therapeutic agent for fibrosis comprises 4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamide or a salt thereof as an active ingredient.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/573,362, filed on Sep. 17, 2019, which is a continuation of U.S.patent application Ser. No. 15/574,060, filed on Nov. 14, 2017 (nowissued as U.S. Pat. No. 10,449,189), which is the National Stage ofInternational Patent Application No. PCT/JP2016/068902, filed on Jun.24, 2016, and claims priority to Japanese Patent Application No.2015-127788, filed on Jun. 25, 2015, all of which are incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a therapeutic agent for fibrosis and apharmaceutical composition for treating fibrosis.

BACKGROUND OF THE INVENTION

Fibrosis is defined as abnormal accumulation of a fibrous tissue causedby e.g., tissue damage and autoimmune reaction. In humans, abnormalaccumulation of a fibrous tissue is found in various organs and tissuessuch as lung, liver, pancreas, kidney, bone marrow and skin.

Lung fibrosis is a disease characterized by diffuse fibroplasia in thealveolar wall and major symptoms such as dry cough and dyspnea onexertion. Lung fibrosis, in a narrow sense, refers to idiopathic lungfibrosis, which is a terminal disease state of interstitial pneumoniaand, in a broad sense, refers to a comorbid state of abnormalaccumulation of a fibrous tissue in lung and interstitial pneumonia. Allinterstitial pneumonitis may be causes of inducing lung fibrosis.

Interstitial pneumonia is a collective term for diseases causinginflammation around the pulmonary interstitium and includes interstitialpneumonia due to specific causes such as infection, collagenosis,radiation, a medicinal agent and dust, and idiopathic interstitialpneumonia due to unknown causes. As the idiopathic interstitialpneumonia, idiopathic lung fibrosis, nonspecific interstitial pneumonia,cryptogenic organized pneumonia, interstitial lung disease accompaniedby respiratory bronchiolitis, desquamative interstitial pneumonia, acuteinterstitial pneumonia and lymphoid interstitial pneumonia, are known.Of these, idiopathic lung fibrosis most frequently occurs and issometimes simply referred to as lung fibrosis.

In idiopathic lung fibrosis, a fibrous connective tissue is diffuselyand excessively formed in the pulmonary interstitium, impairing lungfunction. An average survival period after diagnosis of idiopathic lungfibrosis is reported to be 2.5 to 5 years (Non Patent Document 1). Inparticular, the average survival period after acute exacerbation isextremely short and falls within two months. In lung fibrosis inassociation with an interstitial pneumonia and emphysema, it is reportedthat lung cancer is developed as a complication at a high rate (NonPatent Documents 2, 3).

Interstitial pneumonia induced by a specific cause, can be mostly curedby removing the cause and administering, for example, ananti-inflammatory agent such as a steroid drug. In contrast, lungfibrosis and interstitial pneumonia accompanied by abnormal accumulationof a fibrous tissue is usually treated with a steroid drug and animmunosuppressant. However effective treatments for improving prognosishave not yet been obtained at present and development of a noveltherapeutic agent is desired.

4-[2-Fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideis an antitumor agent with reduced side effects (Patent Document 1) andalso known to exhibit an excellent enhancing activity of an antitumoreffect if used in combination with another antitumor agent (PatentDocument 2). In addition, it is recently found that the compound is alsouseful as a therapeutic agent for osteoporosis (Patent Document 3).

However, it is totally unknown that the compound is effective for lungfibrosis and interstitial pneumonia. In the meantime, it is suggestedthat the symptom of lung fibrosis is improved by administration of HGF(Non Patent Document 2), and that activation of HGF/c-Met is effectivefor treating lung fibrosis (Non Patent Document 4).

CITATION LIST Patent Document

-   [Patent Document 1] international Publication No. WO2009/125597-   [Patent Document 2] International Publication No. WO2013/100014-   [Patent Document 3] International Publication No. WO2015/046484

Non Patent Document

-   [Non Patent Document 1] Pharmacol Ther. 2015 May 3. pii:    S0163-7258 (15) 00091-1-   [Non Patent Document 2] Am J Respir Crit Care Med. 2000 January;    161(1):5-8-   [Non Patent Document 3] Am Rev Tuberc 1957; 76: 559-66-   [Non Patent Document 4] British J. Pharmacology 2011; 163: 141-172

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a therapeutic agent anda pharmaceutical composition exhibiting an excellent prophylactic ortherapeutic effect on fibrosis.

Means for Solving the Problem

The present inventors conducted intensive studies with a view to solvingthe aforementioned problems. As a result, they found that4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof exhibits an effect for suppression of abnormalaccumulation of a fibrous tissue and an inflammation suppression effectassociated therewith and is useful for preventing or treating fibrosisand the inflammation associated therewith.

More specifically, the present invention relates to the following 1) to5).

-   1) A therapeutic agent for fibrosis comprising    4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamide    or a salt thereof as an active ingredient.    1)-2

The therapeutic agent for fibrosis according to 1), wherein the fibrosisis lung fibrosis.

1)-3

The therapeutic agent for fibrosis according to 1) or 1)-2, wherein thefibrosis is interstitial pneumonia accompanied by abnormal accumulationof a fibrous tissue.

1)-4

The therapeutic agent for fibrosis according to 1) to 1)-3, wherein thefibrosis is idiopathic lung fibrosis.

2) A pharmaceutical composition for treating fibrosis, comprising4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof and a pharmaceutically acceptable carrier.

2)-2

The pharmaceutical composition according to 2), wherein the fibrosis islung fibrosis.

2)-3

The pharmaceutical composition according to 2) or 2)-2, wherein thefibrosis is interstitial pneumonia accompanied by abnormal accumulationof a fibrous tissue.

2)-4

The pharmaceutical composition according to 2) to 2)-3, wherein thefibrosis is idiopathic lung fibrosis.

3)4-[2-Fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof for use in treatment of fibrosis.

3)-2

4-[2-Fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof according to 3), wherein the fibrosis is lungfibrosis.

3)-3

4-[2-Fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof according to 3) or 3)-2, wherein the fibrosis isinterstitial pneumonia accompanied by abnormal accumulation of a fibroustissue.

3)-4

4-[2-Fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof according to 3) to 3)-3, wherein the fibrosis isidiopathic lung fibrosis.

4) A pharmaceutical composition for use in treatment of fibrosis,comprising4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof and a pharmaceutically acceptable carrier.

4)-2

The pharmaceutical composition according to 4), wherein the fibrosis islung fibrosis.

4)-3

The pharmaceutical composition according to 4) or 4)-2, wherein thefibrosis is interstitial pneumonia accompanied by abnormal accumulationof a fibrous tissue.

4)-4

The pharmaceutical composition according to 4) to 4)-3, wherein thefibrosis is idiopathic lung fibrosis.

5) A method for treating fibrosis, comprising administering4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof to a patient.

5)-2

The method for treating fibrosis according to 5), wherein the fibrosisis lung fibrosis.

5)-3

The method for treating fibrosis according to 5) or 5)-2, wherein thefibrosis is interstitial pneumonia accompanied by abnormal accumulationof a fibrous tissue.

5)-4

The method for treating fibrosis according to 5) to 5)-3, wherein thefibrosis is idiopathic lung fibrosis.

Effects of the Invention

The compound of the present invention exerts an excellent suppressingeffect on progression of abnormal accumulation of fibrous tissues intissues. Thus, according to the present invention, abnormal accumulationof fibrous tissues can be effectively treated and, in particular,idiopathic lung fibrosis and interstitial pneumonia accompanied byabnormal accumulation of a fibrous tissue can be effectively treated.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 The figure is a graph showing the amount of hydroxyproline inlung tissues.

FIG. 2 The figure is a graph showing scores of abnormal accumulation ofa fibrous tissue in lung tissues.

DETAILED DESCRIPTION OF THE INVENTION

4-[2-Fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideof the present invention (referred to as “the compound of the presentinvention”) or a salt thereof is represented by the following formula(1):

The compound of the present invention is known in the art and can beproduced in accordance with a method described, for example, ininternational Publication No. WO2009/125597 (Patent Document 1).

Examples of the “salt” of the compound of the present invention includean inorganic acid salt, an organic acid salt or an acidic amino acidsalt. Examples of the inorganic acid include hydrochloric acid, sulfuricacid, hydrobromic acid, hydroiodic acid, nitric acid and phosphoricacid. Examples of the organic acid include formic acid, acetic acid,propionic acid, malonic acid, succinic acid, glutaric acid, fumaricacid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid,benzenesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid.Examples of the acidic amino acid include glutamic acid and asparticacid. Among them, an organic acid salt is preferable, a methanesulfonatesalt is more preferable and a monomethanesulfonate salt is particularlypreferable.

The compound of the present invention also includes hydrates, solvatesand crystal polymorphism.

As will be shown later in Examples, the compound of the presentinvention exerts a suppressive effect on abnormal accumulation of afibrous tissue and inflammation suppressive effect in tissues.

Accordingly, the compound of the present invention or a salt thereof isuseful as a medicine exhibiting excellent prophylactic or therapeuticeffects on diseases related to abnormal accumulation of a fibrous tissueand inflammation in tissues, more specifically, as a therapeutic agentfor fibrosis and symptoms associated with fibrosis; and particularly canbe used for preventing or treating diseases associated with abnormalaccumulation of a fibrous tissue in lung tissues, more specifically,lung fibrosis and interstitial pneumonia accompanied by abnormalaccumulation of a fibrous tissue.

In the present invention, examples of fibrosis include lung fibrosis,hepatic fibrosis, abnormal accumulation of a fibrous tissue in pancreas,renal fibrosis, prostatic hyperplasia caused by abnormal accumulation ofa fibrous tissue, bone marrow fibrosis and scleroderma. In thesefibroses, symptoms associated with fibrosis, such as inflammation andatrophy, are observed depending upon the organ with advanced abnormalaccumulation of a fibrous tissue and the rate of progression. Thus,treatment for symptom associated with fibrosis is also included in thepresent invention.

In the present invention, lung fibrosis includes not only idiopathiclung fibrosis but also fibrotic symptom of the lung includingcomorbidity with interstitial pneumonia. More specifically, the lungfibrosis of the present invention includes interstitial pneumoniapossibly causing abnormal accumulation of a fibrous tissue in lung inconjunction therewith.

Examples of such interstitial pneumonia include infectious interstitialpneumonia; interstitial pneumonia associated with collagenosis;interstitial pneumonia associated with radiation exposure; drug-inducedinterstitial pneumonia; idiopathic interstitial pneumonia such asidiopathic lung fibrosis, nonspecific interstitial pneumonia, idiopathicorganized pneumonia, interstitial lung disease accompanied byrespiratory bronchiolitis, desquamative interstitial pneumonia, acuteinterstitial pneumonia and lymphoid interstitial pneumonia. Among them,idiopathic interstitial pneumonia is preferable.

In the present invention, lung fibrosis is preferably chronic situationsof these interstitial pneumonitis (in particular, idiopathicinterstitial pneumonia), interstitial pneumonia accompanied by abnormalaccumulation of a fibrous tissue (in particular, idiopathic interstitialpneumonia), more preferably interstitial pneumonia accompanied byabnormal accumulation of a fibrous tissue (in particular, idiopathicinterstitial pneumonia) and particularly preferably idiopathic lungfibrosis.

In the present invention, lung fibrosis is accompanied by symptoms suchas collagen production, a reduction in lung weight, pulmonaryhypertension and right heart failure. Mitigation of these symptoms isincluded in the present invention. In interstitial pneumonia accompaniedby idiopathic lung fibrosis and abnormal accumulation of a fibroustissue, the levels of serum markers (e.g., KL-6, SP-A, SP-D) are knownto increase. Therefore, in the present invention, therapeutic effectscan be indirectly checked based on the aforementioned symptoms or theserum markers.

In the present invention, abnormal accumulation of a fibrous tissue inliver is caused by hepatocellular damage and hepatitis and includesalcohol-induced hepatic fibrosis, congenital hepatic fibrosis andvirus-induced fibrosis. In the present invention, hepatic fibrosis ispossibly accompanied by hepatitis, fatty liver, liver cirrhosis andhepatic atrophy. Therapies for these symptoms are also included in thepresent invention. Therefore, in the present invention, therapeuticeffect on the aforementioned symptoms can be indirectly checked bymeasuring e.g., the number of platelets in blood, hyaluronic acid andcollagen.

In the present invention, abnormal accumulation of a fibrous tissue inpancreas is abnormal accumulation of a fibrous tissue in the connectivetissue in pancreatic interstitium and include e.g., pancreatic cysticfibrosis. In the present invention, abnormal accumulation of a fibroustissue in pancreas is possibly accompanied by e.g., pancreatitis,pancreatic atrophy and diabetes. Therapies for these symptoms are alsoincluded in the present invention. Therefore, therapeutic effects can beindirectly checked by measuring e.g., trypsin and glucose levels inblood.

In the present invention, examples of renal fibrosis includeglomerulosclerosis, interstitial renal fibrosis and tubulointerstitialfibrosis. In the present invention, renal fibrosis is possiblyaccompanied by e.g., nephritis, renal atrophy and renal failure.Therapies for these symptoms are also included in the present invention.Therefore, in the present invention, therapeutic effects on theaforementioned symptoms can be indirectly checked by measuring e.g.,collagen level in blood.

In the present invention, prostatic hypertrophy induced by abnormalaccumulation of a fibrous tissue is caused by abnormal accumulation of afibrous tissue in the interstitium of prostatic hypertrophy. In thepresent invention, prostatic hypertrophy induced by abnormalaccumulation of a fibrous tissue is possibly accompanied by e.g.,prostatic fibroma, prostatitis and prostatic calcification. Therapiesfor these symptoms are also included in the present invention.

In the present invention, examples of bone marrow fibrosis includeprimary bone marrow fibrosis and idiopathic bone marrow fibrosis. In thepresent invention, bone marrow fibrosis is possibly accompanied by e.g.,splenic tumor, splenic infarction, white erythroblastosis, anemia andportal hypertension. Therapies for these symptoms are also included inthe present invention. Therefore, in the present invention, therapeuticeffects on the aforementioned symptoms can be indirectly checked bymeasuring e.g., red blood cells, platelets and serum LDH in blood.

In the present invention, examples of scleroderma include disseminatedscleroderma and focal scleroderma. In the present invention, sclerodermais possibly accompanied by inflammation of e.g., blood vessels, organfailure, calcification and abnormal accumulation of a fibrous tissue inskin. Therapies for these symptoms are also included in the presentinvention. Therefore, in the present invention, therapeutic effects onthe aforementioned symptoms can be indirectly checked by measuring ananti-nuclear antibody, an anti-topoisomerase I antibody and ananti-centromere antibody.

In the specification, the “therapy” includes not only prevention andtreatment for the aforementioned fibroses but also maintenance forsuppression of progression of abnormal accumulation of a fibrous tissuein tissues, mitigation of inflammation, mitigation of symptom associatedwith fibrosis and relapse prevention.

The compound of the present invention or a salt thereof can be preparedinto either an oral or a parenteral dosage form and can be produced intovarious types of dosing preparations by using a pharmaceuticallyacceptable carrier in accordance with a method known in the art.Examples of the dosage form may include, but are not particularlylimited to, oral agents such as tablets, coated tablets, pills, powders,granules, capsules, liquid preparations, suspensions and emulsions; andparenteral agents such as injections, suppositories and inhalants.

When forming tablets, the following carriers can be used: an excipientsuch as lactose, white sugar, sodium chloride, glucose, urea, starch,calcium carbonate, kaolin, crystalline cellulose and silicic acid; abinder such as water, ethanol, propanol, corn starch, simple syrup,dextrose solution, a starch solution, a gelatin solution,carboxymethylcellulose, shellac, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, potassiumphosphate and polyvinylpyrrolidone; a disintegrant such as dry starch,sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, a polyoxyethylene sorbitan fatty acidester, sodium lauryl sulfate, glycerol monostearate and lactose; adisintegration inhibitor such as white sugar, stearic acid, cacao butterand hydrogenated oil; an absorption promoter such as quaternary ammoniumsalt and sodium lauryl sulfate; a humectant such as glycerin and starch;an adsorbent such as starch, lactose, kaolin, bentonite and colloidalsilicic acid; and a lubricant such as purified talc, a stearate, boricacid powder and polyethylene glycol.

Furthermore, the tablets may be covered with usual coating, ifnecessary; for example, sugar-coated tablets, gelatin-coated tablets,enteric coated tablets, film-coated tablets, double-layered tablets andmultilayered tablets can be prepared.

When forming pills, as the carrier, an excipient such as glucose,lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin andtalc; a binder such as gum Arabic powder, tragacanth powder, gelatin andethanol; and a disintegrant such as laminaran and agar, can be used.Capsules are prepared by charging hard gelatin capsules or soft capsuleswith a mixture with the aforementioned various types of carriers, inaccordance with a routine method.

When preparing liquid preparations, e.g., oral liquid, syrup and elixircan be prepared by using e.g., a flavoring agent, a buffer and astabilizer in accordance with a routine method. In this case, examplesof the flavoring agent may include white sugar, orange peel, citric acidand tartaric acid; examples of the buffer may include sodium citrate;and examples of the stabilizer may include tragacanth, gum Arabic andgelatin.

When preparing suppositories, as the carrier, polyethylene glycol, cocoabutter, a higher alcohol, an ester of a higher alcohol, gelatin and asemisynthetic glyceride can be used.

When preparing injections, a liquid preparation, an emulsion and asuspension are sterilized and preferably they are isotonic fluids withblood. In preparing these dosage forms, as the diluent, water, anaqueous lactic acid solution, ethyl alcohol, propylene glycol, macrogol,ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcoholand a polyoxyethylene sorbitan fatty acid ester can be used.

Note that, in this case, a sufficient amount of salt, glucose orglycerin to prepare an isotonic solution may be added to apharmaceutical preparation or e.g., a solubilizer, a buffer and asoothing agent usually used may be added.

In preparing an inhalation, an aerosol, a powder inhalant and a liquidinhalant are mentioned as a dosage form.

If necessary, a coloring agent, a preservative, a fragrance, a flavoringagent and a sweetening agent; and other pharmaceutical products may beadded to each of these preparations.

Methods for administering the therapeutic agent for fibrosis and thepharmaceutical composition for treating fibrosis of the presentinvention are appropriately determined depending upon e.g., the dosageform; the age, sex and other conditions of the patient; and symptom ofthe patient. For example, tablets, pills, powders, granules, capsules,liquid preparations, suspensions and emulsions are orally administered.Injections are intravenously administered singly or in combination witha general complemental liquid such as glucose and amino acids, andfurther, if necessary, injections are intra-arterially, intramuscularly,intradermally, subcutaneously or intraperitoneally administered bythemselves. Suppositories are intra-rectally administered.

The amount of the compound of the present invention or a salt thereof tobe blended in a unit-dose of a dosage form as mentioned above variesdepending upon the symptom of the patient to be applied or the dosageform; however, the amount per unit dose is desirably about 0.005 to1,000 mg in the case of an oral preparation, about 0.001 to 500 mg inthe case of an injection and about 0.01 to 1,000 mg in the case of asuppository. The dose per day of a medicinal agent having a dosage formas mentioned above varies depending upon e.g., the symptom, body weight,age and sex of the patient and cannot be unconditionally determined;however, the dose/adult/day may be usually about 0.005 to 5,000 mg andpreferably 0.01 to 1,000 mg. This may be preferably administered once aday or daily in about 2 to 4 divided doses.

The present invention will be more specifically described below by wayof Examples and Test Examples; however, the present invention is notlimited to these embodiments.

EXAMPLES Production Example 1: Synthesis of4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamide

In accordance with the production method described in Patent Document 1,4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamidewas synthesized.

Test Example 1: Suppression Effect on Bleomycin-Induced Mouse Pathology(Lung Fibrosis) Model

Mice (C57BL, 6 weeks old) were anesthetized by intraperitoneallyadministrating pentobarbital (50 mg/kg/day), and then bleomycin (20μg/25 μL per mouse) was intra-tracheally sprayed by a sprayer. A weeklater, the mice were anesthetized by inhalation of isoflurane, 0.2 mL ofblood was taken from the eye orbit of the mice. The blood level of asurfactant protein-D (SP-D) was measured. The mice were divided intogroups (9 mice) such that the groups have an equal average SP-D value.

The compound of the present invention was orally administered at each ofdoses of 100 and 200 mg/kg/day, every day for 35 days. In order toconfirm whether a pathological model was established, an untreated group(Normal group) and a Sham group were set up. To the mice of the Shamgroup, physiological saline was intratracheally sprayed in place ofbleomycin. The next day after completion of the final administration,the mice were anesthetized by inhalation of isoflurane and euthanized.Thereafter, the lungs were excised out and subjected to pathologicalanalysis for tissues. Abnormal accumulation of a fibrous tissue wasevaluated and the amounts of hydroxyproline in the tissues weremeasured. The abnormal accumulation of a fibrous tissue was evaluated byusing Ashcroft's method (J Clin Pathol 1988; 41: 467-470).

The hydroxyproline amounts of lung tissues of individual groups areshown in FIG. 1 and scores of abnormal accumulation of a fibrous tissuein the lung tissues are shown in FIG. 2. The mice to which bleomycin wassprayed, the hydroxyproline level of the lung tissues significantlyincreased and scores of abnormal accumulation of a fibrous tissue alsoincreased, compared to the sham group. From this, it was determined thatabnormal accumulation of a fibrous tissue in the lung tissue in mice wasinduced by bleomycin treatment and pathological models are established.

The hydroxyproline amounts of groups to which the compound of thepresent invention was administered at doses of 100 and 200 mg/kg/day,both were significantly low compared to the control group (pathologicalcondition) and their scores of abnormal accumulation of a fibrous tissuewere significantly low. From this, it was suggested that the compound ofthe present invention suppresses abnormal accumulation of a fibroustissue.

According to the above, the compound of the present invention wasdemonstrated to be useful as a therapeutic agent for fibrosis, andparticularly useful as a therapeutic agent for lung fibrosis.

The invention claimed is:
 1. A method for treating abnormal accumulationof a fibrous tissue in liver, comprising administering4-[2-fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof to a patient.
 2. The method according to claim 1,wherein the abnormal accumulation is selected from the group consistingof alcohol-induced hepatic fibrosis, congenital hepatic fibrosis andvirus-induced fibrosis.
 3. The method of claim 1, wherein the4-[2-fluoro-4[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof is orally administered to the patient.
 4. The methodof claim 1, wherein the salt is a methanesulfonate salt.
 5. The methodof claim 1, wherein the salt is a monomethanesulfonate salt.
 6. Themethod of claim 1, wherein 0.005 to 5,000 mg of the4-[2fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof is administered to the patient.
 7. The method of claim1, wherein 0.01 to 1,000 mg of the4-[2fluoro-4-[[[(2-phenylacetyl)amino]thioxomethyl]amino]-phenoxy]-7-methoxy-N-methyl-6-quinolinecarboxamideor a salt thereof is administered to the patient.